This study introduces the prostate cancer linear energy transfer sensitivity index (PCLSI) as a novel method to predict relative biological effectiveness (RBE) in prostate cancer using linear energy transfer (LET) in proton therapy based on screening for DNA repair mutations.

Five prostate cancer cell lines with DNA repair mutations known to cause sensitivity to LET and DNA repair inhibitors were examined using published data. Relative Du145 LET sensitivity data were leveraged to deduce the LET equivalent of olaparib doses. The PCLSI model was built using three of the prostate cancer cell lines (LNCaP, 22Rv1 and Du145) with DNA mutation frequency from patient cohorts. The PCLSI model was compared against two established RBE models, McNamara and McMahon, for LET-optimized prostate cancer treatment plans.

The PCLSI model relies on the presence of eight DNA repair mutations: AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, which are most likely to predict increased LET sensitivity and RBE in proton therapy. In the LET-optimized plan, the PCLSI model indicates that prostate cancer cells with these DNA repair mutations are more sensitive to increased LET than the McNamara and McMahon RBE models, with expected RBE increases ranging from 11%–33% at 2keV/µm.

The PCLSI model predicts increasing RBE as a function of LET in the presence of certain genetic mutations. The integration of LET-optimized proton therapy and genetic mutation profiling could be a significant step toward the use of individualized medicine to improve outcomes using RBE escalation without the potential toxicity of physical dose escalation.

Increasing daylight exposure might be a simple way to improve mental health. However, little is known about daylight-symptom associations in depressive disorders.

In a subset of the Australian Genetics of Depression Study (N = 13,480; 75% female), we explored associations between self-reported number of hours spent in daylight on a typical workday and free day and seven symptom dimensions: depressive (overall, somatic, psychological); hypo-manic-like; psychotic-like; insomnia; and daytime sleepiness. Polygenic scores for major depressive disorder (MDD); bipolar disorder (BD); and schizophrenia (SCZ) were calculated. Models were adjusted for age, sex, shift work status, employment status, season, and educational attainment. Exploratory analyses examined age-stratified associations (18–24 years; 25–34 years; 35–64 years; 65 and older). Bonferroni-corrected associations (p < 0.004) are discussed.

Adults with depression reported spending a median of one hour in daylight on workdays and three hours on free days. More daylight exposure on workdays and free days was associated with lower depressive (overall, psychological, somatic) and insomnia symptoms (p’s<0.001), but higher hypo-manic-like symptoms (p’s<0.002). Genetic loading for MDD and SCZ were associated with less daylight exposure in unadjusted correlational analyses (effect sizes were not meaningful). Exploratory analyses revealed age-related heterogeneity. Among 18–24-year-olds, no symptom dimensions were associated with daylight. By contrast, for the older age groups, there was a pattern of more daylight exposure and lower insomnia symptoms (p < 0.003) (except for 25–34-year-olds on free days, p = 0.019); and lower depressive symptoms with more daylight on free days, and to some extent workdays (depending on the age-group).

Exploration of the causal status of daylight in depression is warranted.

In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.

The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

The suicide rate in the elderly population is the highest of all ages in Korea. Suicide prevention programs specialized in the elderly are scarce.

We evaluated the effect of the suicidal prevention program named “Nae-an-ae” (means to love oneself), which was specifically designed for the conditions of the community dwelling elderly.

The subjects were those who agreed to participate in the Nae-an-ae program among those evaluated as suicide high-risk groups according to the 2021 Jeollanam-do Mental Health Survey. The program consisted of five sessions of simple activities that could be practiced in daily life along with knowledge transfer through education on emotion recognition, stress management, sleep and relaxation, pain and exercise, and depression. This program was conducted by social workers or nurses working at each local community mental health and welfare center. We evaluated the Geriatric Depression Scale-Short Form Korean Version (GDS-SF), suicidal ideation, satisfaction with life scale (SWLS) and brief resilience scale (BRS) which were measured before and after the program and compared them with the control group.

A total of 276 participated in the program, 226 were in the control group. In the program participating group, the frequency of suicidal ideation was significantly decreased from 36.2% to 11.6% after the program. GDS-SF, SWLS and BRS were significantly decreased in active group than control group.

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These findings showed that “Nae-an-ae” program was found to affect not only the control of suicide risk factors such as depression but also positive factors such as life satisfaction and resilience.

None Declared

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD).

To investigate the genomic architecture of ASD in terms of non-coding de novo mutations and 3-dimensional chromatin interactions

We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions.

Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development.

Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

None Declared

Several studies have reported on the feasibility and impact of e-monitoring using computers, or smartphones, in patients with mental disorders, including Bipolar Disorder (BD). Despite some promising early results, concerns have been raised about the motivation and ability of patients with BD to adhere to e-monitoring, in particular when they are depressed or manic. While studies on e-monitoring have examined the role of demographic factors, such as age, gender, or socioeconomic status and use of health apps, to our knowledge, no study has examined clinical characteristics that might impact adherence with e-monitoring of patients with BD.

We analyzed adherence to e-monitoring in patients with BD who participated in an ongoing e-monitoring study and evaluated whether demographic and clinical factors would predict adherence.

Eighty-seven participants with BD in different phases of the illness were included. Patterns of adherence for wearable use, daily and weekly self-rating scales over 15 months were analyzed to identify adherence trajectories using growth mixture models (GMM). Multinomial logistic regression models and Multiple Component Analyses were fitted to compute the effects of predictors on GMM classes.

Adherence rates were 79.5% for the wearable; 78.5% for weekly self-ratings; and 74.6% for daily self-ratings. GMM identified three latent class subgroups: (i) participants with good adherence with the protocol; (ii) participants with partial adherence; (iii) participants with poor adherence. Women, participants with a history of suicide attempt, and those with a history of inpatient admission were more likely to belong to the group with good adherence.

Participants with higher illness burden (e.g., history of admission to hospital, history of suicide attempts) have higher adherence rates to e-monitoring. This is important because our findings debunk myths around illness burden as an obstacle to adhere to e-monitoring studies. Participants might have seen e-monitoring as a tool for better documenting symptom change and better managing their illness, thus motivating their engagement.

None Declared

Lamina-specific alterations of inhibitory circuitries have been considered the crucial pathogenesis of perceptual, cognitive and behavioral symptoms presented in schizophrenia and mood disorders. Especially, with emerging evidences indicating the close lamina-specific relationship between synaptic defects and γ-Aminobutyric acid (GABA)-related gene dysfunctions, it has been suggested the mRNA dysregulations of Tyrosine kinase B (TrkB) and Glutamate decarboxylase 67 (GAD67) could particularly be implicated in middle and deep layers of neocortex of patients with major psychiatric disorders.

Giving inquiries of whether defects of these mRNA levels in Orbitofrontal cortex (OFC) would be involved as lamina-specific patterns in individuals with schizophrenia and mood disorders.

We examined mRNA levels of BDNF, TrkB and GAD67 in each OFC layer I through VI. We analyzed data from postmortem brain tissue of the Stanley Neuropathology Consortium Integrative Database (SNCID). SNCID consists of 15 subjects in each of four groups (schizophrenia, bipolar disorder, major depression without psychotic features, and unaffected controls). All groups were matched for age, sex, race, brain pH and post-mortem interval.

We found TrkB mRNA levels to be significantly reduced in layer VI in both groups with schizophrenia (25.8%) and bipolar disorder (35.7%) compared with controls. GAD67 mRNA levels were also significantly reduced in layer III and IV in patients with schizophrenia (23.4% and 22.7%, respectively) and bipolar disorder (31.2% and 24.9%, respectively) compared with controls. Individuals with major depression showed only trends toward decreased mRNA levels of GAD67 in layer III and IV and of TrkB in layer VI compared with controls. TrkB mRNA levels in layer VI were significantly correlated with GAD67 mRNA levels in layer III (ρ=0.581, p=0.037) and IV (ρ=0.857, p<0.001) in subjects with bipolar disorder, but not in those with schizophrenia. When analyzed with partial correlation controlling the effects of pH and PMI, significance of correlation remained only between GAD67 mRNA in layer IV and TrkB mRNA in layer VI in individuals with bipolar disorder (ρ=0.768, p=0.006).

The resulting lamina-specific decreases in inhibitory tone across layers of OFC may contribute to the unrestrained irritability and violent behaviors in common shared by both patients with schizophrenia and bipolar disorder. Nonetheless, our findings indicate the obvious correlations between lamina-specifically altered TrkB and GAD67 mRNA levels in OFC might be a candidate for endophenotype of bipolar disorder.

None Declared

Olanzapine (OLA) is a common first-prescribed antipsychotic and has shown favorable efficacy in acutely exacerbated patients with schizophrenia. The mixed receptor activity of OLA and its greater affinity for serotonin 5-HT2A rather than dopamine D2 receptors are similar to those of clozapine. Pharmacokinetically, OLA is metabolized mainly by hepatic cytochrome enzyme P450 1A2 (CYP1A2). Because risks of antipsychotic polypharmacy include increased drug-drug interactions, pharmacokinetic considerations are important for selection of antipsychotics to be combined. Due to its pharmacological characteristics, amisulpride (AMI), another atypical antipsychotic with proven efficacy, is a promising adjuvant agent of special interest. AMI is unlikely to interact with other drugs due to the low plasma protein binding and metabolism and does not affect the activity of the CYP system. Furthermore, AMI is highly selective for dopamine D2/D3 receptors; has minimal or no affinity for D1, D4, or D5 receptors. Despite the potential benefits of the combination of OLA and AMI, only a few open-label studies have been conducted, and no randomized clinical trial has been performed to date to examine the efficacy and tolerability of the combination. Hence, the goals of this study were to test the hypothesis that AMI augmentation would improve psychotic symptoms and be well tolerated in schizophrenic patients who showed poor response to OLA monotherapy.

The purpose of this study was to compare the efficacy and tolerability of continued olanzapine (OLA) versus amisulpride (AMI) augmentation in schizophrenic patients with poor response to OLA monotherapy.

The present 4-week, randomized, rater-blinded study included 25 patients with schizophrenia who were partially or completely unresponsive to treatment with OLA monotherapy. Eligible subjects were randomly assigned at a 1:1 ratio to continuation of OLA monotherapy (OLA group) or OLA with AMI augmentation (AMI group). Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at 1, 2, and 4 weeks.

The changes in PANSS total score and PANSS-positive subscale score were significantly different (p < 0.05) between the OLA and AMI groups. The differences between the two groups in PANSS-negative subscale, PANSS-general subscale, Brief Psychiatric Rating Scale, and Clinical Global Impression-Severity (CGI-S) scale scores were not statistically significant.

AMI augmentation could be an effective strategy for patients with schizophrenia who show inadequate early response to OLA monotherapy.

W.-M. Bahk Grant / Research support from: Handok Pharmaceuticals, Seoul, Korea, Y. S. Woo: None Declared, S.-Y. Park: None Declared, B.-H. Yoon: None Declared, S.-M. Wang: None Declared, M.-D. Kim: None Declared

Dental healthcare personnel (DHCP) are at high risk of exposure to coronavirus disease 2019 (COVID-19). We sought to identify how DHCP changed their use of personal protective equipment (PPE) as a result of the COVID-19 pandemic, and to pilot an educational video designed to improve knowledge of proper PPE use.

The study comprised 2 sets of semistructured qualitative interviews.

The study was conducted in 8 dental clinics in a Midwestern metropolitan area.

In total, 70 DHCP participated in the first set of interviews; 63 DHCP participated in the second set of interviews.

In September–November 2020 and March–October 2021, we conducted 2 sets of semistructured interviews: (1) PPE use in the dental community during COVID-19, and (2) feedback on the utility of an educational donning and doffing video.

Overall, 86% of DHCP reported having prior training. DHCP increased the use of PPE during COVID-19, specifically N95 respirators and face shields. DHCP reported real-world challenges to applying infection control methods, often resulting in PPE modification and reuse. DHCP reported double masking and sterilization methods to extend N95 respirator use. Additional challenges to PPE included shortages, comfort or discomfort, and compatibility with specialty dental equipment. DHCP found the educational video helpful and relevant to clinical practice. Fewer than half of DHCP reported exposure to a similar video.

DHCP experienced significant challenges related to PPE access and routine use in dental clinics during the COVID-19 pandemic. An educational video improved awareness and uptake of appropriate PPE use among DHCP.

Subthreshold/attenuated syndromes are established precursors of full-threshold mood and psychotic disorders. Less is known about the individual symptoms that may precede the development of subthreshold syndromes and associated social/functional outcomes among emerging adults.

We modeled two dynamic Bayesian networks (DBN) to investigate associations among self-rated phenomenology and personal/lifestyle factors (role impairment, low social support, and alcohol and substance use) across the 19Up and 25Up waves of the Brisbane Longitudinal Twin Study. We examined whether symptoms and personal/lifestyle factors at 19Up were associated with (a) themselves or different items at 25Up, and (b) onset of a depression-like, hypo-manic-like, or psychotic-like subthreshold syndrome (STS) at 25Up.

The first DBN identified 11 items that when endorsed at 19Up were more likely to be reendorsed at 25Up (e.g., hypersomnia, impaired concentration, impaired sleep quality) and seven items that when endorsed at 19Up were associated with different items being endorsed at 25Up (e.g., earlier fatigue and later role impairment; earlier anergia and later somatic pain). In the second DBN, no arcs met our a priori threshold for inclusion. In an exploratory model with no threshold, >20 items at 19Up were associated with progression to an STS at 25Up (with lower statistical confidence); the top five arcs were: feeling threatened by others and a later psychotic-like STS; increased activity and a later hypo-manic-like STS; and anergia, impaired sleep quality, and/or hypersomnia and a later depression-like STS.

These probabilistic models identify symptoms and personal/lifestyle factors that might prove useful targets for indicated preventative strategies.